A multi-looping chromatin signature predicts dysregulated gene expression in neurons with familial Alzheimer's disease mutations.
A multi-looping chromatin signature predicts dysregulated gene expression in neurons with familial Alzheimer's disease mutations.
复制标题
多环染色质特征可预测患有家族性阿尔茨海默病突变的神经元中基因表达失调。
DOI：
10.1101/2024.02.27.582395
复制
发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Phillips-Cremins,JenniferE
中科院分区：
文献类型：
--
作者：
Chandrashekar,Harshini;Simandi,Zoltan;Choi,Heesun;Ryu,Han-Seul;Waldman,AbrahamJ;Nikish,Alexandria;Muppidi,SrikarS;Gong,Wanfeng;Paquet,Dominik;Phillips-Cremins,JenniferE
哺乳动物基因组折叠成成千上万个长距离环，但它们的功能作用和生理相关性仍然知之甚少。在这里，使用具有罕见家族性阿尔茨海默病（FAD）突变的人类有丝分裂后神经元，我们在淀粉样蛋白积累和tau蛋白磷酸化之前确定了数百个可重复失调的基因和数千个错误连接的环。单个环不能预测表达变化;然而，mRNA水平和单细胞爆发频率变化的严重程度和方向与FAD获得或丢失的启动子-增强子环的数量密切相关。经典的建筑蛋白CTCF和cohesin不改变占用FAD突变神经元。相反，我们意外地发现TAATTA基序服从DLX同源结构域转录因子的结合，并在FAD动态启动子-增强子环改变非编码RNAPolII信号。DLX 1/5/6 mRNA水平在FAD突变神经元中强烈上调，这与兴奋性至抑制性基因表达的转变以及连接增强子与神经亚型基因的多环错误连接一致。DLX 1过表达足以导致野生型神经元中的环路错误布线，包括分别具有串联TAATTA阵列和单一TAATTA基序的增强子处的丢失和获得的环路。我们的数据揭示了人类神经元同源工程罕见FAD突变谱系承诺过程中多环布线错误和失调的兴奋性和抑制性转录程序之间的基因组结构-功能关系。
Mammalian genomes fold into tens of thousands of long-range loops, but their functional role and physiologic relevance remain poorly understood. Here, using human post-mitotic neurons with rare familial Alzheimer’s disease (FAD) mutations, we identify hundreds of reproducibly dysregulated genes and thousands of miswired loops prior to amyloid accumulation and tau phosphorylation. Single loops do not predict expression changes; however, the severity and direction of change in mRNA levels and single-cell burst frequency strongly correlate with the number of FAD-gained or -lost promoter-enhancer loops. Classic architectural proteins CTCF and cohesin do not change occupancy in FAD-mutant neurons. Instead, we unexpectedly find TAATTA motifs amenable to binding by DLX homeodomain transcription factors and changing noncoding RNAPolII signal at FAD-dynamic promoter-enhancer loops. DLX1/5/6 mRNA levels are strongly upregulated in FAD-mutant neurons coincident with a shift in excitatory-to-inhibitory gene expression and miswiring of multi-loops connecting enhancers to neural subtype genes. DLX1 overexpression is sufficient for loop miswiring in wildtype neurons, including lost and gained loops at enhancers with tandem TAATTA arrays and singular TAATTA motifs, respectively. Our data uncover a genome structure-function relationship between multi-loop miswiring and dysregulated excitatory and inhibitory transcriptional programs during lineage commitment of human neurons homozygously-engineered with rare FAD mutations.